3-hydroxy-4-alkyloxyphenyl heterocyclic aromatic carboxylates

ABSTRACT

Novel 3-hydroxy-4-alkyloxphenyl heterocyclic aromatic carboxylate compounds particularly well suited as sweeteners in foodstuff.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a novel group of compounds and more particularto a novel group of compound particularly well suited as sweeteners inedible foodstuff.

2. Description of the Prior Art

Sweetness is one of the primary taste cravings of both animals andhumans. Thus, the utilization of sweetening agents in foods in order tosatisfy this sensory desire is well established.

Naturally occurring carbohydrate sweeteners such as sucrose, are stillthe most widely used sweetening agents. While these naturally occurringcarbohydrates, i.e., sugars, generally fulfill the requirements of sweettaste, the abundant usage thereof does not occur without deleteriousconsequence, e.g., high caloric intake and nutritional imbalance. Infact, oftentimes the level of these sweeteners required in foodstuffs isfar greater than the level of the sweetener that is desired foreconomic, dietic or other functional consideration.

In an attempt to eliminate the disadvantages concomitant with naturalsweeteners, considerable research and expense have been devoted to theproduction of artificial sweeteners, such as for example, saccharin,cyclamate, dihydrochalcone, aspartame, etc. While some of theseartificial sweeteners satisfy the requirements of sweet taste withoutcaloric input, and have met with considerable commercial success, theyare not, however, without their own inherit disadvantages. For example,many of these artificial sweeteners have the disadvantages of high cost,as well as delay in the perception of the sweet taste, persistentlingering of the sweet taste, and a very objectionable bitter, metallicaftertaste when used in food products.

Since it is believed that many disadvantages of artificial sweeteners,particularly aftertaste, is a function of the concentration of thesweetener, it has been previously suggested that these effects could bereduced or eliminated by combining artificial sweeteners such assaccharin, with other ingredients or natural sugars, such as sorbitol,dextrose, maltose etc. These combined products, however, have not beenentirely satisfactory either. Some U.S. Patents which disclose sweetenermixtures include for example, U.S. Pat. No. 4,228,198; U.S. Pat. No.4,158,068; U.S. Pat. No. 4,154,862; U.S. Pat. No. 3,717,477.

Also much work has continued in an attempt to develop and identifycompounds that have a sweet taste. For example, in Yamato, et al.,Chemical Structure and Sweet Taste of Isocoumarin and Related Compounds,Chemical Pharmaceutical Bulletin, Vol. 23, p. 3101-3105 (1975) and inYamato et al. Chemical Structure and Sweet Taste Of Isocoumarins andRelated Compound, Chemical Senses and Flavor, Vol. 4 No. 1, p. 35-47(1979) a variety of sweet structures are described. For example,3-Hydroxy-4-methoxybenzyl phenyl ether is described as having a faintsweet taste.

Despite the past efforts in this area, research continues. Accordingly,it is desired to find a compound that provides a sweet taste when addedto foodstuff or one which can reduce the level of sweetener normallyemployed and thus eliminate or greatly diminish a number ofdisadvantages associated with prior art sweeteners.

SUMMARY OF THE INVENTION

This invention pertains to sweetness compounds of the structure:##STR1## wherein: R is selected fom the group consisting of methyl andethyl;

R₁ is selected from the group consisting of ##STR2## wherein n is aninterger from 0 to b 1; each Z is selected from the group consisting ofS, O, NR₂, N and CR₂ with the proviso that at least one Z is a heteroatom and with a further proviso that NR₂ is not NH; and

each R₂ is selected from the group consisting of H, CH₃, CH₂ CH₃, CH₂CH₂ CH₃, CH(CH₃)₂, OH, OCH₃, OCH₂ CH₃, OCH(CH₃)₂, CH₂ OH, CH₂ CH₂ OH,CH₂ CHOHCH₃, CH₂ OCH₃, CHO, COCH₃, COCH₂ CH₃, CH₂ COCH₃, COOH and COOCH₃with the proviso that R₁ contain no more than 12 carbon atoms; and saltsthereof.

Most of the compounds of the formula described herein above aresweeteners, the sweetness of which is many times that of comparableamounts of sucrose. The sweetness of compounds of the formula can bereadily determined by a simple test procedure described herein.

Several compounds of the formula when tested for sweetness showedlittle, if any, sweetness to sucrose, whereas most compounds havegreater sweetness than sucrose, e.g., 100-300 times greater. Compoundsin which R₁ is 2-pyrrolecarboxylate and 3-pyrrolecarboxylate show nosweetness and are not within the preview of this invention. In general,the sweetener compound should possess a sweetness at least five timesgreater and preferably at least thirty times and more preferably 100times greater than sucrose on comparable weight basis.

These compounds in addition to having a sweet taste, function as a lowcalorie sweetening agent when employed with a foodstuff.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, the novel compounds areselected from the group consisting of; ##STR3## wherein: R is selectedfrom the group consisting of methyl and ethyl;

R₁ is selected from the group consisting of ##STR4## wherein n is aninterger from 0 to 1;

Z is selected from the group consisting of S, O, NR₂, N and CR₂ with theproviso that at least one Z is a hetero atom; and

R₂ is selected from the group consisting of H, CH₃, CH₂ CH₃, CH₂ CH₂CH₃, CH(CH₃)₂, OH, OCH₃, OCH₂ CH₃, OCH(CH₃)₂, CH₂ OH, CH₂ CH₂ OH, CH₂CHOHCH₃, CH₂ OCH₃, CHO, COCH₃, COCH₂ CH₃, CH₂ COCH₃, COOH and COOCH₃with the proviso that R₁ contain no more than 12 carbon atoms; and saltsthereof.

Preferably R₁ will contain no more than 10 carbon atoms and morepreferably will contain no more than 8 carbon atoms.

Illustrative compounds within the above formula include:

3-hydroxy-4-ethoxyphenyl 2-furoate

3-hydroxy-4-methoxyphenyl 2-furoate

3-hydroxy-4-methoxyphenyl 2-thiophenecarboxylate

3-hydroxy-4-methoxyphenyl 3-thiophenecarboxylate

3-hydroxy-4-methoxyphenyl 3-furoate

3-hydroxy-4methoxyphenyl 5-methyl-2-furoate

3-hydroxy-4-methoxyphenyl 5-methyl-2-thiophenecarboxylate

3-hydroxy-4-methoxyphenyl 2-isopropyl-2-thiophenecarboxylate

3-hydroxy-4-methoxyphenyl 2-thienylacetate

3-hydroxy-4-methoxyphenyl N-acetyl-2-pyrrolecarboxylate

3-hydroxy-4-methoxyphenyl 5-acetyl-2-thienoate

3-hydroxy-4-methoxyphenyl 5-methoxy-2-thiophenecarboxylate

3-hydroxy-4-methoxyphenyl 3,5-dimethyl-2-thiophenecarboxylate

3-hydroxy-4-methoxyphenyl 2-thiazolecarboxylate

3-hydroxy-4-methoxyphenyl 5-thiazolecarboxylate

3-hydroxy-4-methoxyphenyl 2-oxazolecarboxylate

3-hydroxy-4-methoxyphenyl 2-imidazolecarboxylate

3-hydroxy-4-methoxyphenyl 2-furylacetate

3-hydroxy-4-methoxyphenyl 2-pyrrylacetate

These novel compounds are effective sweetness agents when used alone orin combination with other sweeteners in foodstuffs. For example, othernatural and/or artificial sweeteners which may be used with the novelcompounds of the present invention include sucrose, fructose, corn syrupsolids, dextrose, xylitol, sorbitol, mannitol, acetosulfam, thaumatin,invert sugar, saccharin, cyclamate, dihydrochalcone, aspartame(L-aspartyl-L-phenylalanine methyl ester) and other dipeptides,glycyrrhizin and stevioside and the like.

Typical foodstuffs, including pharmaceutical preparations, in which thesweetness agents of the present invention may be used are, for example,beverages including soft drinks, carbonated beverages, ready to mixbeverages and the like, infused foods (e.g. vegetables or fruits),sauces, condiments, salad dressings, juices, syrups, desserts, includingpuddings, gelatin and frozen desserts, like ice creams, sherbets andicings, confections, toothpaste, mouthwash, chewing gum, intermediatemoisture foods (e.g. dog food) and the like.

In order to achieve the effects of the present invention, the compoundsdescribed herein are generally added to the food product at a levelwhich is effective to perceive sweetness in the food stuff and suitablyis in an amount in the range of from about 0.0001 to 2% by weight basedon the consumed product. Greater amounts are operable but not practical.Preferred amounts are in the range of from about 0.0005 to about 1% ofthe foodstuff. Generally, the sweetening effect provided by the presentcompound is experienced over a wide pH range, e.g. 2 to 10 preferably 3to 7 and in buffered and unbuffered formulations.

It is preferred then when the compounds are used in the foodstuff thatthe compounds have a sucrose equivalent of at least 2 percent by weight,more preferrably that they have a sucrose equivalent of at least 5percent by weight and most preferrably they have a sucrose equivalent ofat least 8 percent by weight.

A taste procedure for determination of sweetness merely involves thedetermination of sucrose equivalency.

Sucrose equivalence for sweetener are readily determined. For example,the amount of a sweetener that is equivalent to 10 weight percentaqueous sucrose can be determined by having a panel of tasters taste thesolution of a sweetener and match its sweetness to the standard solutionof sucrose. Obviously, sucrose equivalents for other than 10 weightpercent are determined by matching the appropriate sucrose solutions.

It is desired that when the sweetening agent of this invention isemployed in combination with another sweetener the sweetness equivalenceof the other sweetener is equal to or above about 2 percent sucroseequivalence. Preferably the combination of sweeteners provides a sucroseequivalence in the range of from about 3 weight percent to about 25weight percent and most preferably 4 weight percent to about 15 weightpercent.

In order to prepare the compounds of the present invention anesterification reaction is employed. A 3-benzyloxy-4-R-oxyphenol isesterified with an acid form or acid chloride form of the R₁ moiety(e.g. R₁ CO₂ H or R₁ COCl). This provides a 3-benzyloxy -4-R-oxyphenylR₁ -carboxylate. The 3-benzyloxy moiety is subsequently converted to thedesired 3-hydroxy-4-R-oxyphenyl R₁ -carboxylate.

For example, when R is methyl then 3-benzyloxy-4-methoxyphenol is usedfor the esterification reaction. To obtain 3-benzyloxy-4-methoxyphenol,isovanillin which is also known 3-hydroxy-4-methoxybenzaldehyde is usedas a starting material. Isovanillin is a commercially availablematerial. If R is to be other than methyl then the appropriate 4-alkoxycompound is used as the starting material. The 4-alkoxy compound is madeby alkylation of 3,4-dihydroxybenzaldehyde which is commerciallyavailable. Isovanillin is converted to 3-benzyloxy-4-methoxybanzaldehydewhich is then converted to 3-benzyloxy-4-methoxyphenyl formate by thefollowing reactions.

Performic acid is prepared by first heating a mixture of 30% by weighthydrogen peroxide and 97% by weight formic acid in a weight ratio of 1:5to 60° C. and then cooling the mixture in an ice both. The mixture isthen added dropwise over a three hour period to an ice-cold 1 M solutionof 3-benzyloxy-4-methoxybenzaldehyde in methylene chloride. After theaddition is completed a saturated solution of sodium bisulfite is addeddropwise until the mixture exhibits a negative starch-iodide test forperoxides. The reaction mixture is poured into an equal volume of water.The phases separate and the aqueous phase is extracted with two twoparts of methylene chloride per part of aqueous phase. The combinedorganic phases are washed with water, dried over magnesium sulfate andthe solvent is evaporated. The 3-benzyloxy -4-methoxyphenyl formate isrecrystallized from 95% by weight ethanol.

The 3-benzyloxy-4-methoxyphenyl formate is then converted to3-benzyloxy-4-methoxyphenol by the following reaction. A mixture of3-benzyloxy-4-methoxyphenyl formate, methanol and 1 M sodium hydroxidein a weight ratio of 1:6:10 is heated under reflux conditions for onehour, the mixture is allowed to cool and an equal volume of water isadded. The solution is washed with ether and acidified to pH 3 withconcentrated hydrochloric acid. The resulting mixture is extracted withether. The combined extracts are washed with water and dried overmagnesium sulphate and the solvent is evaporated to yield a tan solidwhich is 3-benzyloxy-4-methoxyphenol.

The 3-benzyloxy -4-methoxyphenol is reacted with the R₁ acid or the R₁acid chloride according to one of the following reactions. When an R₁acid is to be used, the phenol (1.0 equiv.), triethylamine (1.1 equiv.)and 4-dimethylaminopyridine (0.1 equiv.) are first dissolved inmethylene chloride. The desired R₁ acid chloride (1.1 equiv.) is addedand the mixture is stirred for 12 hours. The mixture is then washed with1 M hydrochloric acid, saturated sodium bicarbonate and water and driedover magnesium sulfate. The solvent is evaporated to yield the desiredproduct which may be purified by chromotography if necessary.

If an R₁ acid is to be used then a solution of the phenol (1.0 equiv.),carboxylic acid (1.1 equiv.) and 4-dimethylaminopyridine (0.1 equiv.) inmethylene chloride is first stirred at 0° C. Dicyclohexylcarbodiimide(1.1 equiv.) is added and the mixture allowed to warm slowly to roomtemperature overnight. The mixture is filtered to removedicyclohexylurea. The filtrate is washed with 1 M hydrochloric acid,saturated sodium bicarbonate and water and then is dried over magnesiumsulfate. The solvent is evaporated to yield the desired product whichmay be purified by chromatography if necessary.

In order to obtain the desired product it is necessary to remove thebenzyl protecting group. The benzyl group can be removed by one of twomethods. In one method the benzyl protected compound is suspended in 95percent ethanol and 10 percent palladium on carbon is added. The mixtureis placed on a Parr hydrogenator which is then charged with hydrogen toa pressure of approximately 50 lbs. per square inch. Upon the cessationof hydrogen uptake (approximately 2-5 hours) the mixture is filteredthrough a Celite pad and the solvent evaporated to yield the desiredproduct which may be purified by chromatography if necessary.

In another method of removing the benzyl protecting group a solution ofthe benzyl protected ester (1 equiv.) in methylene chloride is stirredat room temperature under argon atmosphere. Iodotrimethylsilane (1.3equiv.) is added and the reaction mixture stirred for 12 hours. Thereaction is then quenched with methanol and stirred for thirty minutes.The solvent is then evaporated and the residue dissolved in ether. Thissolution is washed with 1 M hydrochloric acid, saturated sodiumbicarbonate and water, dried over magnesium sulfate and the solvent isevaporated. The product is purified by column chromatography over siliagel.

Further details are described in McMurry et al. Journal ChemicalSociety, pages 1491-8 (1960) and Robinson et al. Journal ChemicalSociety, pages 3163-7 (1931).

The requisite acid or acid chloride forms of the desired R₁ moiety areeither commercially available, known in the art, or prepared fromcommercially available starting materials by known synthetic procedures.

Commercially available carboxylic acid precursors can be found in, Chem.Sources U.S.A., Directories Publishing Co., Inc. Ormond Beach, Fla. aswell as Chem. Sources Europe, Chem. Sources Europe Publisher, MountainLakes, N.J.

Carboxylic acids, in general, can be prepared by a host of syntheticprocedures from other available starting materials. Examples of thesemethods including specifics and reaction conditions can be found in,Survey of Organic Synthesis, Vols. 1 and 2, C. Buehler & D. Pearson,Wiley Interscience Inc., New York and Advanced Organic Chemistry;Reactions, Mechanisms and Structure, J. March, McGraw-Hill, New York.

In addition to these referenced methods carboxylic acids can be obtainedby conversion of other chemical functionalities. A reference for theinterconversion of chemical functionalities can be found in, Compendiumof Organic Synthetic Methods, Vols, I & II, I. T. Harrison & S.Harrison, Wiley Interscience Inc., New York.

The present new compounds form salts due to the presence of the phenolichydroxy group. Thus, metal salts can be formed by reaction with alkalisuch as aqueous ammonia, alkali and alkaline earth metal compounds suchas sodium, potassium and calcium oxides, hydroxides, carbonates andbicarbonate. The salts are of higher aqueous solubility than the parentcompound and are useful for purification or isolation of the presentproducts.

The following examples are presented to further illustrate thisinvention.

EXAMPLE I

The compound 3-hydroxy-4-methoxyphenyl 2-furoate was made as follows. Anamount of 2.00 gms. of 3-benzyloxy-4-methoxyphenol, 1.00 gms. oftriethylamine and 0.10 gms of 4-dimethylaminopyridine were dissolved in100 ml. of methylene chloride at 0° C. and stirred. To the mixture wasadded 1.16 gms. of 2-furoyl chloride and the mixture was stirredovernight. The mixture was then washed wth equal volumes of 1 Mhydrochloric acid, saturated sodium bicarbonate and water. The mixturewas then dried over magnesium sulfate and the solvent evaporated toyield 3-benzyloxy-4-methoxyphenyl 2-furoate.

This benzyl protected compound was then deprotected by suspending it in100 ml of 95% by weight ethanol and then adding 10% by weight palladiumon carbon. The mixture was placed on a Parr hydrogenator which was thencharged with hydrogen gas to a pressure of approximately 50 lbs/in².After 3 hours the hydrogen uptake ceased and the mixture was filteredthrough a Celite pad. The solvent was evaporated to yield3-hydroxy-4-methoxyphenyl-2-furoate. The product was purified by columnchromatography. The structure was confirmed employing nuclear magneticresonance (NMR) methods.

Aqueous solutions were prepared with 0.010 and 0.05 weight percent ofthe product and it was determined by a panel of experts that thesolutions had a sucrose equivalencies of 3 and 4 gms. wt. %respectively.

EXAMPLE II

This example pertains to the making of 3-hydroxy-4-methoxyphenyl2-thiophenecarboxylate. This compound was prepared by adding 2.00 gms.of 3-benzyloxy-4-methoxyphenol, 1.14 gms. of 2-thiophenecarboxylic acid,and 0.16 gms. of 4-dimethylaminopyridine to 50 ml of methylene chloridewhich was stirred at 0° C. To the mixture was added 1.90 gms. ofdicyclohexylcarbodiimide and the mixture was allowed to warm slowly toroom temperature overnight. The mixture was then filtered to removedicyclohexylurea and the filtrate was washed with 1 M hydrochloric acid,saturated sodium bicarbonate, and water. It was then dried overmagnesium sulfate, and evaporated to yield the phenol protected product.This was deprotected by dissolving the product in 50 ml of methylenechloride and adding 0.86 gms. if iodotrimethylsilane. After stirringovernight, the reaction was quenched by adding 5 ml. of methanol. Afterstirring for 30 minutes, the solvent was evaporated and the residuedissolved in ether. This solution was washed with equal volumes ofsaturated sodium bicarbonate, 1 M hydrochloric acid and water, and driedover magnesum sulfate. The solvent was then evapoated and the residuepurified by column chromatography to yield 0.3 gms. of3-hydroxy-4-methoxyphenyl 2-thiophenecarboxylate. The structure wasconfirmed employing NMR.

To an aqueous solution was added 0.005 weight percent of the product andit was determined by a panel of experts to have a sucrose equivalency of4 weight percent.

EXAMPLE III

In this example 3-hydroxy-4-methoxyphenyl 3-thiophenecarboxylate wasprepared substantially as Example II except that 2.00 gms. of3-benzyloxy-4-methoxyphenol where coupled with 1.14 gms. of3-thiophenecarboxylic acid. The structure was confirmed employing NMR.

To an aqueous solution was added 0.01 weight percent of this product anda panel of experts determined it to have a sucrose equivalency of 5.0weight percent sucrose.

EXAMPLE IV

In this example 3-hydroxy-4-methoxyphenyl 5methyl-2-thiophenecarboxylatewas prepared substantially as in Example II except that 1.27 gms. of5-methyl-2-thiophenecarboxylic acid was coupled to 2.00 gms of3-benzyloxy-4-methoxyphenol. The compound was purified with columnchromatography and its structure confirmed using NMR.

An amount of 0.005 weight percent of 3-hydroxy-4-methoxyphenyl5-methyl-2-thiophenecarboxylate was were added to aqueous solutions andthe solutions were determined to have a sucrose equivalency of 3 weightpercent sucrose.

EXAMPLE V

In this Example 3-hydroxy-4-methoxyphenyl N-methylpyrrole-2-carboxylatewas prepared by adding 1.80 gms of N-methylpyrrole-2-carboxylic acid,3.00 gms of 3-benzyloxy-4-methoxyphenol and 0.24 gms.4-dimethylaminopyridine to 50 ml of methylene chloride which was stirredat 0° C. To the mixture was added 2.88 gms. of dicyclohexylcarbodimideand the mixture was allowed to warm slowly to room temperatureovernight. The mixture was then filtered to remove dicyclohexylurea andthe filtrate was washed with 1 M hydrochloric acid, saturated sodiumbicarbonate and water. It was then dried over magnesium sulfate, andevaporated to yield the phenol protected product. This protected phenolwas then suspended in 100 ml of 95% ethanol and 10% palladium on carbonwas added. The mixture was placed on a Parr hydrogenator which was thencharged with hydrogen to a pressure of about 50 lbs/in². Upon thecessation of hydrogen uptake the mixture was filtered and the solventevaporated wherein 1.25 gms. of 3-hydroxy-4-methoxyphenylN-methylpyrrole-2 -carboxylate was prepared. The structure was confirmedusing NMR.

To an aqueous solution was added 0.010 weight percent of the purifiedproduct and a panel of experts determined it to have a sucroseequivalence of 2 weight percent sucrose.

EXAMPLE VI

In this Example 3-hydroxy-4-methoxyphenyl 3-thienylacetate was preparedsubstantially as in Example II except that 2.04 gms of 3-thienylaceticacid was coupled to 3.0 gms of 3-benzyloxy-4-methoxyphenol. Thestructure was confirmed employing NMR.

To an aqueous solution was added 0.005% of the above made product and itwas determined to have a sucrose equivalency of 2 percent.

EXAMPLE VII

In this Example 3-hydroxy-4-methoxyphenyl 2-thienylacetate was preparedas described in Example II except that 3 gms of 3-benzyloxy4-methoxyphenol was coupled to 2.04 gms. of 2-thienylacetic acid. Theproduct structure was confirmed by NMR.

To an aqueous solution was added 0.005 weight percent of this productand was determined to have a sucrose equivalency of 2 weight percentsucrose.

EXAMPLE XVIII

A cherry flavored beverage is prepared by mixing 1.48 gms. of anunsweetened cherry flavored instant beverage base mix wth 438 gms. ofwater, 0.13 gms aspartame (APM) and 0.044 gms. (0.01 weight percent) of3-hydroxy-4-methoxyphenyl 2-thiophenecarboxylate. The base contains amalic acid and monocalcium phosphate buffer.

EXAMPLE XIX

A mixed fruit gelatin is prepared by mixing 5.16 gms. of unsweetenedgelatin base mix with 237 gms. of water 0.07 gms. (0.029 weight percent)saccharin and 0.024 gms. (0.01 weight percent) of3-hydroxy-4-methoxyphenyl 2-furoate. The gelatin base contains an adipicacid and disodium phosphate buffer.

EXAMPLE XXIII

A vanilla flavored pudding is prepared by mixing 474 gms. of milk, 21.7gms. of an unsweetened pudding base mix containing 1.35 gms. of sodiumacid pyrophosphate, 36.0 gms. sucrose (6.8 weight percent) and 0.027gms. (0.005 weight percent) of 3-hydroxy-4-methoxyphenyl2-thiophenecarboxylate.

What is claimed is:
 1. A compound of the formula: ##STR5## wherein R isselected from the group consisting of methyl and ethyl;R₁ is selectedfrom the group consisting of: ##STR6## wherein n is an integer from 0 to1; each Z is selected from the group consisting of S, O NR₂, N and CR₂with the provisio that at least one Z is a hetero atom and a furtherprovisio that NR₂ is not a NH group; and each R₂ is selected from thegroup consisting of H, CH₃, CH₂ CH₃, CH₂ CH₂ CH₃, CH(CH₃)hd 2, OH, OCH₃,OCH₂ CH₃, OCH(CH₃)₂, CH₂ OH, CH₂ CH₂ OH, CH₂ CHOHCH₃, CH₂ OCH₃, CHO,CHOCH₃, CHOCH₂ CH₃, CH₂ COCH₃ COOH and COOCH₃ with R₁ containing no morethan 12 carbon atoms; and salts thereof.
 2. A compound according toclaim 1 with the proviso that R₁ contain no more than 10 carbon atoms.3. A compound according to claim 1, with the proviso that R₁ contain nomore than 8 carbon atoms.
 4. 3-hydroxy-4-methoxyphenyl2-thiophenecarboxylate.
 5. 3-hydroxy-4-methoxyphenyl 2-furoate. 6.3-hydroxy-4-methoxyphenyl 5-methyl-2-thiophenecarboxylate. 7.3-hydroxy-4-methoxyphenyl 3-thiophenecarboxylate. 8.3-hydroxy-4-methoxyphenyl N-methylpyrrole-2-carboxylate. 9.3-hydroxy-4-methoxyphenyl 3-thienylacetate. 10.3-hydroxy-4-methoxyphenyl 2-thienylacetate.